NEUROVASCULAR REGULATION AND HYPERTENSION: Studies during the previous funding period have focused on the mechanisms responsible for the coupling between neural activity and cerebral blood flow in the normal state. In this renewal application we propose to study the alteration in neurovascular coupling that occur during elevations in arterial pressure. Hypertension exerts deleterious effects on the structure and function of the central nervous system, the cerebral circulation being a major target of these actions. The long-term goal of this project is to define the mechanisms by which hypertension alters the regulation of the cerebral circulation during neural activity and how these alterations affect the structure and function of the central nervous system. We will begin by testing the hypothesis that angiotensin II, a major mediator of hypertension, impairs the mechanisms responsible for the increase in cerebral blood flow induced by neural activation. In particular, the proposed studies will seek to determine whether Ang II exerts this effect by acting directly on cerebral blood vessels and impairing their ability to react to vasodilator signals generated by neural activity. The following specific hypotheses will be tested: (1) angiotensin 11 alters the "coupling" between cerebral blood flow and neural activity, (2) this effect is mediated by angiotensin II-induced production of reactive oxygen species in cerebral blood vessels, and (3) NAD(P)H oxidase is a major source of the vascular reactive oxygen species contributing to the dysfunction. Studies will be conducted in mice in which arterial pressure is elevated by acute or chronic administration of angiotensin II. The increase in cerebral blood flow produced in the somatosensory cortex by whisker stimulation will be used as a model of neural activation. Cerebrovascular responses to endothelium-dependent and independent vasodilators, and production of reactive oxygen species in cerebral blood vessels will also be studied. Mice overexpressing superoxide dismutase-1 will be used to examine the role of reactive oxygen species, and mice lacking the gp91phox subunit of NAD(P)H oxidase will be used to determine whether this enzyme is the source of the radicals. The results of these studies will enhance our understanding of the effects of hypertension on the brain and may provide new insights into treatment strategies aimed at counteracting these detrimental actions.